19-51455564-A-G

Variant names:

• chr19-51455564-A-G
• NM_014442.3:c.905T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014442.3(SIGLEC8):​c.905T>C​(p.Leu302Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.378

Genes affected

SIGLEC8 (HGNC:10877): (sialic acid binding Ig like lectin 8) Sialic acid-binding immunoglobulin (Ig)-like lectins, or SIGLECs (e.g., CD33 (MIM 159590)), are a family of type 1 transmembrane proteins each having a unique expression pattern, mostly in hemopoietic cells. SIGLEC8 is a member of the CD33-like subgroup of SIGLECs, which are localized to 19q13.3-q13.4 and have 2 conserved cytoplasmic tyrosine-based motifs: an immunoreceptor tyrosine-based inhibitory motif, or ITIM (see MIM 604964), and a motif homologous to one identified in signaling lymphocyte activation molecule (SLAM; MIM 603492) that mediates an association with SLAM-associated protein (SAP; MIM 300490) (summarized by Foussias et al., 2000 [PubMed 11095983]).[supplied by OMIM, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC8	NM_014442.3	c.905T>C	p.Leu302Pro	missense_variant	Exon 4 of 7	ENST00000321424.7	NP_055257.2
SIGLEC8	NM_001363548.1	c.626T>C	p.Leu209Pro	missense_variant	Exon 3 of 6		NP_001350477.1
SIGLEC8	XM_011526734.3	c.872T>C	p.Leu291Pro	missense_variant	Exon 4 of 7		XP_011525036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.905T>C	p.Leu302Pro	missense_variant	Exon 4 of 7	1	NM_014442.3	ENSP00000321077.2
SIGLEC8	ENST00000340550.5	c.626T>C	p.Leu209Pro	missense_variant	Exon 3 of 6	1		ENSP00000339448.4
SIGLEC8	ENST00000430817.5	c.578T>C	p.Leu193Pro	missense_variant	Exon 2 of 6	2		ENSP00000389142.1
SIGLEC8	ENST00000597352.1	n.521T>C		non_coding_transcript_exon_variant	Exon 3 of 3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.905T>C (p.L302P) alteration is located in exon 4 (coding exon 4) of the SIGLEC8 gene. This alteration results from a T to C substitution at nucleotide position 905, causing the leucine (L) at amino acid position 302 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	.;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.00068	T
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	.;M;.
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Benign	0.063
Sift	Uncertain	0.018	D;D;T
Sift4G	Uncertain	0.045	D;D;D
Polyphen		1.0	D;P;D
Vest4		0.26
MutPred		0.83		.;Gain of glycosylation at S299 (P = 0.0414);.;
MVP		0.28
MPC		0.55
ClinPred		0.69	D
GERP RS		1.1
Varity_R		0.47
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-51958818;